Vinblastine 20″ amides: synthetic analogs that maintain or improve potency and simultaneously overcome Pgp-derived efflux and resistance

Abstract

A vinca alkaloid compound substituted at the 20′-position with a carboxamido group is disclosed. The carbonyl of the carboxamido group is bonded to a 20′-amino group and to a ring system that contains up to three 5-, 6- or 7-membered rings that are fused or otherwise bonded together. Each ring can be carbocyclic or heterocyclic, with a heterocyclic ring containing up to three hetero ring atoms that are the same or different and are selected from nitrogen, oxygen and sulfur. The ring system can include up to four substituent groups other than hydrogen that are discussed within. Methods of preparing the compounds are disclosed as are compositions for their use and methods of treatment using d compound. A particularly preferred compound has an activity in specified cancer cell growth inhibition assays that is the same or better than its parental, unsubstituted vinca compound and is not subject to Pgp-mediated efflux.

The invention claimed is: 
     
       1. A 20′-carboxamide-substituted vinca alkaloid compound or a pharmaceutically acceptable salt thereof, wherein said compound corresponds in structure to a compound shown in Table A, below, 
       
         
           
                 
               
                   TABLE A 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                 
                 
                 
                 
               
                   Vinca Compound 
                   R 1   
                   R 2   
                   R 3   
                 
                     
                 
                   Vinblastine 
                   —CH 3   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   Vincristine 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   Vindesine 
                   —CH 3   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   —OH 
                 
                     
                 
             
                
                
               
               
                
                
               
            
             
                
                
                
                
                
                
                
                
               
            
           
         
       
       wherein
 Y— is fluoro (—F) or hydrido (—H), and 
 R a — is a ring system containing up to a total of three 5-, 6- or 7-membered rings that are fused or otherwise directly bonded to each other, 
 said ring system being carbocyclic or heterocyclic in which ring atoms other than carbon are the same or different and are nitrogen (N), oxygen (O) or sulfur (S), and said heterocyclic ring system contains up to three ring heteroatoms, and 
 up to four substituents that are the same or different are present bonded to ring atoms of said ring system, said substituents being selected from the group consisting of C 1 -C 7  hydrocarbyl, trifluoromethyl, phenyl, halogen (fluoro, chloro or bromo), cyano, nitro, C 1 -C 7  acyl, amino, mono- or di-C 1 -C 7  hydrocarbylamino, a nitrogen-bonded heterocyclic ring of 5- or 6 members that can contain 1 or 2 additional ring hetero atoms selected from oxygen, nitrogen, and sulfur, acylamido containing 1-7 carbon atoms, sulfonylamido containing 1-7 carbon atoms, oxycarbonylamido containing 1-7 carbon atoms, C 1 -C 7  hydrocarbyloxy, N—C 1 -C 7  hydrocarbyl acylamido containing 1-7 carbon atoms in the acyl group, N—C 1 -C 7  hydrocarbyl sulfonylamido containing 1-7 carbon atoms in the sulfonamido group, N—C 1 -C 7  hydrocarbyl oxycarbonylamido containing 1-7 carbon atoms in the oxycarbonyl group, trifluoromethoxy, trifluoromethylamino, trifluoromethylamino oxycarbonyl containing 1-7 carbon atoms in the oxycarbonyl group, and C 1 -C 7  hydrocarbylthioxy group. 
 
     
     
       2. The 20′-carboxamide-substituted vinca alkaloid compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein said ring system contains one or two rings. 
     
     
       3. The 20′-carboxamide-substituted vinca alkaloid compound or pharmaceutically acceptable salt thereof according to  claim 2 , wherein said ring system contains one aromatic ring. 
     
     
       4. The 20′-carboxamide-substituted vinca alkaloid compound or pharmaceutically acceptable salt thereof according to  claim 3 , wherein said one aromatic ring is carbocyclic. 
     
     
       5. The 20′-carboxamide-substituted vinca alkaloid compound or pharmaceutically acceptable salt thereof according to  claim 4 , wherein said one carbocyclic aromatic ring is a single 6-membered ring. 
     
     
       6. The 20′-carboxamide-substituted vinca alkaloid compound or pharmaceutically acceptable salt thereof according to  claim 4 , wherein said compound corresponds in structure to a compound shown in Table A, below, 
       
         
           
                 
               
                   TABLE A 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                 
                 
                 
                 
               
                   Vinca Compound 
                   R 1   
                   R 2   
                   R 3   
                 
                     
                 
                   Vinblastine 
                   —CH 3   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   Vincristine 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   Vindesine 
                   —CH 3   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   —OH 
                 
                     
                 
             
                
                
               
               
                
                
               
            
             
                
                
                
                
                
                
                
                
               
            
           
         
       
       wherein
 Y— is fluoro (—F) or hydrido (—H), and 
 R a — is a ring system selected from the group consisting of one or more of those shown below: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       7. The 20′-carboxamide-substituted vinca alkaloid compound or pharmaceutically acceptable salt thereof according to  claim 4 , wherein said ring system contains two fused rings at least one of which is an aromatic carbocyclic ring. 
     
     
       8. The 20′-carboxamide-substituted vinca alkaloid compound or pharmaceutically acceptable salt thereof according to  claim 7 , wherein said compound corresponds in structure to a compound shown in Table A, below, 
       
         
           
                 
               
                   TABLE A 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                 
                 
                 
                 
               
                   Vinca Compound 
                   R 1   
                   R 2   
                   R 3   
                 
                     
                 
                   Vinblastine 
                   —CH 3   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   Vincristine 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   Vindesine 
                   —CH 3   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   —OH 
                 
                     
                 
             
                
                
               
               
                
                
               
            
             
                
                
                
                
                
                
                
                
               
            
           
         
       
       wherein
 Y— is fluoro (—F) or hydrido (—H), and 
 R a — is a ring system selected from the group consisting of one or more of those shown below: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       9. The 20′-carboxamide-substituted vinca alkaloid compound or pharmaceutically acceptable salt thereof according to  claim 5 , wherein said aromatic carbocyclic ring is bonded directly to the depicted carbonyl group. 
     
     
       10. The 20′-carboxamide-substituted vinca alkaloid compound or pharmaceutically acceptable salt thereof according to  claim 9 , wherein a heterocyclic ring is fused to said carbocyclic aromatic ring. 
     
     
       11. The 20′-carboxamide-substituted vinca alkaloid compound or pharmaceutically acceptable salt thereof according to  claim 10 , wherein said compound corresponds in structure to a compound shown in Table A, below, 
       
         
           
                 
               
                   TABLE A 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                 
                 
                 
                 
               
                   Vinca Compound 
                   R 1   
                   R 2   
                   R 3   
                 
                     
                 
                   Vinblastine 
                   —CH 3   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   Vincristine 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   Vindesine 
                   —CH 3   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   —OH 
                 
                     
                 
             
                
                
               
               
                
                
               
            
             
                
                
                
                
                
                
                
                
               
            
           
         
       
       wherein
 Y— is fluoro (—F) or hydrido (—H), and 
 R a — is a ring system selected from the group consisting of one or more of those shown below: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       12. The 20′-carboxamide-substituted vinca alkaloid compound or pharmaceutically acceptable salt thereof according to  claim 3 , wherein said at least one aromatic ring is heterocyclic. 
     
     
       13. The 20′-carboxamide-substituted vinca alkaloid compound or pharmaceutically acceptable salt thereof according to  claim 12 , wherein said heterocyclic aromatic ring contains 5-members. 
     
     
       14. The 20′-carboxamide-substituted vinca alkaloid compound or pharmaceutically acceptable salt thereof according to  claim 13 , wherein said 5-membered heterocyclic aromatic ring contains two heteroatoms in the ring. 
     
     
       15. The 20′-carboxamide-substituted vinca alkaloid compound or pharmaceutically acceptable salt thereof according to  claim 12 , wherein said heterocyclic aromatic ring contains 5- or 6-members and contains one hetero atom in the ring. 
     
     
       16. The 20′-carboxamide-substituted vinca alkaloid compound or pharmaceutically acceptable salt thereof according to  claim 12 , wherein said compound corresponds in structure to a compound shown in Table A, below, 
       
         
           
                 
               
                   TABLE A 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                 
                 
                 
                 
               
                   Vinca Compound 
                   R 1   
                   R 2   
                   R 3   
                 
                     
                 
                   Vinblastine 
                   —CH 3   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   Vincristine 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   Vindesine 
                   —CH 3   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   —OH 
                 
                     
                 
             
                
                
               
               
                
                
               
            
             
                
                
                
                
                
                
                
                
               
            
           
         
       
       wherein
 Y— is fluoro (—F) or hydrido (—H), and 
 R a — is a ring system selected from the group consisting of one or more of those shown below: 
 
       
         
           
           
               
               
           
         
       
     
     
       17. The 20′-carboxamide-substituted vinca alkaloid compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein said ring system, Ra-, is free of substituents other than fluoro bonded at a ring position beta- to the depicted carbonyl group to which Ra- is bonded. 
     
     
       18. The 20′-carboxamide-substituted vinca alkaloid compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein the substituents present are electron donating. 
     
     
       19. The 20′-carboxamide-substituted vinca alkaloid compound or pharmaceutically acceptable salt thereof according to  claim 1 , wherein Y— is fluoro. 
     
     
       20. The 20′-carboxamide-substituted vinca alkaloid compound or pharmaceutically acceptable salt thereof according to  claim 19 , wherein said compound corresponds in structure to a compound shown in Table A, below, 
       
         
           
                 
               
                   TABLE A 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                 
                 
                 
                 
               
                   Vinca Compound 
                   R 1   
                   R 2   
                   R 3   
                 
                     
                 
                   Vinblastine 
                   —CH 3   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   Vincristine 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   Vindesine 
                   —CH 3   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   —OH 
                 
                     
                 
             
                
                
               
               
                
                
               
            
             
                
                
                
                
                
                
                
                
               
            
           
         
       
       wherein
 R a — is a ring system selected from the group consisting of those shown below: 
 
       
         
           
           
               
               
           
         
       
     
     
       21. A pharmaceutical composition that comprises a cancerous cell proliferation-inhibiting amount of a 20′-carboxamide-substituted vinca alkaloid compound of  claim 1  or a pharmaceutically acceptable salt thereof dissolved or dispersed in a physiologically acceptable carrier. 
     
     
       22. A method of inhibiting the growth of cancerous cells that comprises contacting said cancerous cells with a cancerous cell proliferation-inhibiting amount of a 20′-carboxamide-substituted vinca alkaloid compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
       23. The method according to  claim 22 , wherein said cancerous cells are contacted a plurality of times. 
     
     
       24. The method according to  claim 22 , wherein said cancerous cells are contacted in vitro. 
     
     
       25. The method according to  claim 22 , wherein said contacted cancerous cells are leukemia cells. 
     
     
       26. The method according to  claim 22 , wherein said contacted cancerous cells are colon cancer cells. 
     
     
       27. The method according to  claim 22 , wherein said contacted cancerous cells are non small cell lung cancer cells. 
     
     
       28. The method according to  claim 22 , wherein said contacted cancerous cells are colon cancer cells that overexpress phosphoglycoprotein (Pgp).